Antiviral drug

Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Many common plants such as St John's wort are also widely believed in naturopathic circles to be viricides, but evidence to support this is far from sufficient in scientific circles. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil and its constituents. Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses (best known for causing cold sores and genital herpes, but actually the cause of a wide range of other diseases, such as chicken pox), the hepatitis B and C viruses, which can cause liver cancer, and influenza A and B viruses. Researchers are working to extend the range of antivirals to other families of pathogens. Designing safe and effective antiviral drugs is difficult, because viruses use the host's cells to replicate. This makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells. Moreover, the major difficulty in developing vaccines and anti-viral drugs is due to viral variation. The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the intense pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of the deadly acquired immunodeficiency syndrome (AIDS) pandemic. Like antibiotics for bacteria, antiviral drugs are a class of antimicrobials used specifically for treating viral infections. They are relatively harmless to host because they inhibit the development of pathogens instead of destroying them. Most of the antiviral agents need to be activated by viral and cellular enzymes before exerting antiviral effect. Hence, activity of enzymes and concentration of substrates will influence the efficacy of these drugs. In majority of acute infections, viral replication is already at its peak when symptoms appear. To be effective, antiviral therapy has to be started in the incubation period, i.e has to be prophylactic.

virus 297x300 ANTIVIRAL DRUGS: Classification and Anti Herpes Virus drugs Antiviral

CLASSIFICATION:
1. Anti-herpes virus: Idoxuridine, acyclovir, valacyclovir, famciclovir. 2. Anti-retrovirus : Zidovudine (AZT), Didanosine, Nevirapine, Ritonavir, Indinavir. 3. Anti-influenza virus: Amatidine, Rimantadine. 4. Nonselective antiviral drugs: Ribavirin, Lamivudine, Interferon alpha. General Mechanism of Action of Nucleoside Analogues: 1. Taken up by cells 2. Converted by viral and cellualr enzymes to the triphosphate form 3. The triphosphate form inhibits: a. DNA polymerase b. Reverse transcriptase c. RNA polymerase 4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.

ROLE OF AGENTS IN THERAPY:
ANTI-HERPES VIRUS DRUGS: Idoxuridine, acyclovir, valacyclovir, famciclovir, ganciclovir, forscarnet. Except forscarnet which is an inhibitor of DNA polymerase and reverse transcriptase, others are purine and pyrimidine anlaogues. Classification: 1. Acyclovir and Valaciclovir: These are guanine analogues with antiviral activities against Herpes group only. Mechanism of action: Acyclovir –viral thymidine kinase–> AcycloGMP –cellular kinases–> AcycloGTP AcycloGTP performs 2 functions: a. Inhibits viral DNA polymerase competitively b. Termination of DNA synthesis by incorporation into DNA

Mechanism of resistance development: a. Reduced activity of viral thymidine kinase b. Altered DNA polymerase Use: The activity of acyclovir on herpes group: Herpes simplex type I > Herpes simplex type II > (Varicella-zoster virus = Epstein-Barr virus) Cytomegalovirus (CMV) are practically not affected. a. Genital Herpes simplex (type II) b. Mucocutaneous H. simplex (type I) : remains localized to lips and gums c. H.simplex encephalitis (type I) d. H. simplex (type I) keratitis : because of good corneal penetration e. Herpes zoster f. Chickenpox Adverse effects: a. Topical: stinging and burning sensation b. Oral: headache, nausea, malaise c. Intravenous: rashes, sweating, emesis and fall in BP d. Other toxicities: i. Renal insufficiency (normalization on discontinuation of drug) ii. Encephalopathy : tremors, lethargy, disorientation, hallucinations, convulsions and coma Valaciclovir is an ester prodrug of acyclovir with improved oral bioavailability. It is the drug of choice in herpes zoster. 2. Famciclovir: It is used an alternative to acyclovir for genital or orolabial herpes and herpes zoster. 3. Ganciclovir: a. Analogue of acyclovir b. Active against all herpes viruses including CMV c. CMV can develop ganciclovir resistance by mutation d. Low oral bioavailability given I.V. e. Drug of choice for CMV infection in immunosupressed patients (eg. AIDS) : pneumonia, colitis, retinitis Adverse effects: a. Bone marrow supression : leukopenia and thrombocytopenia b. CNS effects: headache, behavioral psychosis, coma, convulsions

c. Rashes, fever, vomiting 4. Idoxuridine and Trifluridine: a. Topical agent for Herpes keratitis b. Triflurdine (also for CMV) is better for H.simplex II keratoconjunctivits 5. Forscarnet: a. Direct inhibitor of DNA polymerase and reverse transcriptase b. An inorganic pyrophosphate analogue ADR: a. Nephrotoxicity (Renal diabetes like condition, acute renal failure) b. Hypocalcemia, hypokalemia and hypomagnesemia c. Anemia d. Tremor, convulsions e. Phlebitis (administered i.v.) Use: a. CMV retinitis and other CMV infections resistant to gancyclovir b. H.simplex and Varicella Zoster resistant to acyclovir c. HIV

Anti-retrovirus:
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART. The American National Institutes of Health and other organizations recommend offering antiretroviral treatment to all patients with AIDS. Classification of Anti-retrovirus: Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits: • Entry inhibitors (or fusion inhibitors) : They interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class.

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CCR5 receptor antagonists: They are the first antiretroviral drugs which do not target the virus directly. Instead, they bind to the CCR5 receptor on the surface of the T-Cell and block viral attachment to the cell. Most strains of HIV attach to T-Cells using the CCR5 receptor. If HIV cannot attach to the cell, it cannot gain entry to replicate.

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Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transciptase inhibitors (NtRTI): They are nucleoside and nucleotide analogues which inhibit reverse transcription by being incorporated into the newly synthesized viral DNA strand as faulty nucleotides; they both act as competitive substrate inhibitors.

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Non-Nucleoside reverse transcriptase inhibitors (NNRTI): They inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase.

Protease inhibitors (PIs): They target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for the final assembly of new virions.

Integrase inhibitors: They inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell.

Maturation inhibitors: They inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Because these viral particles have a defective core, the virions released consist mainly of noninfectious particles. Alpha interferon is a currently available agent in this class